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Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma

FREDRIK HEDBORG^*,,1, ERIK ULLERÅS^*,, LARS GRIMELIUS^*, ERIK WASSBERG, PATRICK H MAXWELL, BARBARA HERO^#, FRANK BERTHOLD^#, FREIMUT SCHILLING^¶, DIETER HARMS^**, BENGT SANDSTEDT and GARY FRANKLIN^,

Departments of
^* Genetics and Pathology, Rudbeck Laboratory,
Women and Child Health, University Hospital,
Animal Development and Genetics, Evolutionary Biology Centre, and
Medical Cell Biology, Biomedical Centre, University of Uppsala, SE 751 85 Uppsala, Sweden; ^||Renal Section, Hammersmith Campus, Imperial College, London, Great Britain;
^# Department of Pediatrics, University of Cologne, D-50924 Köln, Germany;
^¶ Department of Pediatric Hematology and Oncology, Olgahospital, D-70176 Stuttgart, Germany;
^** Department of Pediatric Pathology, Christian-Albrecht’s University in Kiel, D-24042 Kiel, Germany;
Childhood Cancer Research Unit, Karolinska Institute, SE 17176 Stockholm, Sweden; and
Biacore AB, SE-754 50 Uppsala, Sweden

¹Correspondence: Department of Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. E-mail: fredrik.hedborg{at}genpat.uu.se

We present evidence that in neuroblastoma, a pediatric malignancy of embryonal sympathetic origin, hypoxia, underlies a phenotypic switch from a primitive neuronal to a chromaffin cell type. This conclusion is based on morphological and molecular data on 116 clinical tumors and is supported by data on the phenotypic effects of hypoxia on neuroblastoma cell lines when studied in monolayer culture and as tumor xenografts. In the clinical material, extensive chromaffin features were seen in regions of chronic tumor hypoxia. This was the exclusive form of intra-tumoral maturation of stroma-poor tumors and was also seen in stroma-rich tumors, either exclusively or in combination with ganglion-like cells. In neuroblastoma cell lines, hypoxia induced changes in gene expression associated with the chromaffin features observed in vivo. We therefore propose tumor hypoxia as a major cue determining phenotype in sympathetic tumors of neuroblastic origin. Because it appears to be reversible upon reoxygenation in monolayer culture, we suggest the term metaplasia for the phenomenon.—Hedborg, F., Ullerås, E., Grimelius, L., Wassberg, E., Maxwell, P. H., Hero, B., Berthold, F., Schilling, F., Harms, D., Sandstedt, B., Franklin, G. Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma.

Key Words: angiogenesis • differentiation • sympathetic nervous system • insulin-like growth factor • vascular-endothelial growth factor

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